DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 08/17/2026 has been entered.
Claims 11, 13, 15, 16, 22 and 24-38 are pending in this application and were examined on their merits.
The rejection of Claim(s) 11, 13, 15, 22, 24, 25, 27, 28, 29, 32, 33, 34, 35, 36 and 38 under 35 U.S.C. § 103 as being unpatentable over Konrath et al. (US 7,718,380 B2), of record, in view of Zhuo et al. (WO 2015/123598 A1), cited in the IDS, Yang et al. (1997), Terzi et al. (US 2015/0258127 A1) and Jiang et al. (2016), all of record, has been withdrawn due to the Applicant’s amendment to the claims filed 08/17/2026.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim(s) 11, 13, 15, 22, 24, 25, 27, 28, 29, 32, 33, 34, 35, 36 and 38 are rejected under 35 U.S.C. § 103 as being unpatentable over Konrath et al. (US 7,718,380 B2), of record, in view of Zhuo et al. (WO 2015/123598 A1), cited in the IDS, Yang et al. (1997), Terzi et al. (US 2015/0258127 A1) and Jiang et al. (2016), all of record, and further in view of Cojocaru et al. (2010) and Contois et al. (2014).
Konrath et al. teaches a composition/system comprising: a patient tacrolimus
(whole) blood sample mixed with a hemolytic/extraction agent containing a detergent
mix of the 1.0% TRITON® X-100 (octylphenoxypolyethoxy ethanol) and 0.5%
deoxycholate (Column 7, Lines 16-29), and reading on Claims 11, 22, 24, 27, 28, 32
and 33.
With regard to Claims 11, 24, 28, 34, 35 and 36, Konrath et al. further teaches, "In general, the concentration of detergent should be in the range of about 0.1% to about 3.0% w/v, and preferably about 0.3% to about 1.0%, during the RBC lysis step, and the concentration of extracting agent (deoxycholate or other aqueous detergents) should be in the range of about 0.3% to about 1%, preferably about 0.4% to about 0.6% during the extraction step" (Column 5, Lines 12-23).
Thus, the composition of Konrath et al. either anticipates the claim limitations of "about 0.05-0.25% deoxycholate" and "the ratio of octylphenoxypolyethoxy ethanol to deoxycholate is 4:1 or 1.0:0.25%) as the reference-taught amount of 0.5% deoxycholate would be considered "about" or "approximately" 0.25% (lacking a definition for "about" in the Specification, giving the term its' broadest, reasonable interpretation) or in the alternative, the limitation is made obvious by the reference disclosure of "about 0.3-1.0% and "about 0.4-0.6%" extracting agent (deoxycholate or other aqueous detergents)" which would overlap and obviate the claimed concentration range. See the MPEP at 2144.05, I.
With regard to Claims 11 and 38, Konrath et al. further teaches that tacrolimus forms complexes with other blood plasma constituents such as immunophilins, albumin and lipoproteins and in order to assay tacrolimus the tacrolimus/protein complexes must be dissociated to release tacrolimus (Column 1, Lines 47-53).
The teachings of Konrath et al. were discussed above.
Konrath et al. did not teach that the composition further comprises anti-Lp-PLA2 antibodies (binding molecules), as required by Claims 11, 13, 24, 25 and 28;
or that the sample is a serum sample, as required by Claims 11 and 38.
Zhuo et al. teaches a method of diagnosing cardiovascular disease (CVD) in a subject based on the level of Lp-PLA2 (Abstract);
an anti-Lp-PLA2 antibody (Pg. 22, Paragraph [0096]); and that detergent can readily make Lp-PLA2 from a biological sample, such as a blood sample available for assay (e.g. may dissociate Lp-PLA2 from the lipoproteins LDL and HDL) (Pg. 18, Paragraph [0078]).
Yang et al. teaches that blood serum contains both albumin and lipoprotein (Pg, 507, Abstract).
Terzi et al. teaches the determination of tacrolimus serum levels by radioimmunoassay (Pg. 9, Paragraph [0103]).
Jiang et al. teaches that Lp-PLA2 is found in (blood) serum (Pg. 5, 3rd Paragraph).
Cojocaru et al. teaches that approximately 80% of Lp-PLA2 circulates bound to LDL, while the remaining 20% is bound to HDL (Pg. 52, Column 1, Lines 31-35),
the reference further teaches that Lp-PLA2 is associated mainly with apolipoprotein B (apoB)-containing lipoproteins and primarily with LDL (Pg. 53, Column 2, Lines 35-40).
Contois et al. teaches the use of an anti-apoB immunoprecipitant (LIPOSEP IP™) to remove non-HDL (e.g. LDL) particles from a sample (Pg. 348, Abstract and Column 2, Lines 21-22).
It would have been obvious to those of ordinary skill in the art before the invention to modify the composition/system of Konrath et al. comprising a tacrolimus patient (whole) blood sample mixed with a hemolytic/extraction agent containing 1.0% of the detergent TRITON® X-100 and 0.5% (or about 0.25%) of the detergent deoxycholate to modify the method to use a blood serum sample because Konrath further teaches that tacrolimus forms complexes with other blood plasma constituents such as immunophilins, albumin and lipoproteins and in order to assay tacrolimus the tacrolimus/protein complexes must be dissociated to release tacrolimus. Terzi et al. teaches that blood serum may be used to assay tacrolimus in blood serum and Yang et al. teaches that blood serum contains both lipoprotein and albumin. Those of ordinary skill in the art would have recognized that blood serum, in addition to whole blood and plasma, may be used as a sample to assay tacrolimus. However, as taught by Konrath above, before assay the tacrolimus must be dissociated from complex with proteins (such as albumin and lipoprotein) found in the blood serum.
Those of ordinary skill in the art would have been motivated to make this modification to assay tacrolimus in a patient blood serum sample based on the availability of samples and artisan preference. There would have been a reasonable expectation in making this modification because tacrolimus can be assayed in both whole blood, plasma and serum.
It would have been further obvious to those of ordinary skill in the art before the
invention to modify the composition/system of Konrath et al., Yang et al. and Terzi et al.
comprising a tacrolimus patient serum sample mixed with a hemolytic/extraction agent
containing 1.0% of the detergent TRITON® X-100 and 0.5% (or about 0.25%) of the
detergent deoxycholate with the addition of; anti-Lp-PLA2 antibodies (binding
molecules) as taught by Zhuo et al. and an anti-apoB immunoprecipitant, as taught by Cojocaru et al. and Contois et al. because this would provide a composition which
would also enable detection of Lp-PLA2 in the tacrolimus serum sample and which has been depleted to the primary binding lipoprotein for Lp-PLA2 (apoB-associated HDL).
Jiang et al. teaching that blood serum contains Lp-PLA2. Those of ordinary skill in the art would have been motivated to make this modification in order to additionally assess the tacrolimus patient serum sample for a biomarker of cardiovascular disease.
There would have been a reasonable expectation of success in making this modification because Konrath et al. teaches the use of a detergent mix as a hemolysis/extraction agent to dissociate tacrolimus from protein in a blood sample, Zhuo et al. teaches that detergent also makes Lp-PLA2 in blood sample available for assay, Cojocaru et al. teaches that the majority of Lp-PLA2 is bound by HDL, Contois et al. teaches that LDL can be removed by an immunoprecipitant and Jiang et al. teaches
that blood serum also contains Lp-PLA1.
With regard to the limitations of Claims 11, 15, 28 and 29, it would be inherent in the composition/system of Konrath et al. that the amount of detergent in the detergent/blood mixture would result in 5% or less and/or 0.1-1% or less of the Lp-PLA2 molecules in the blood sample being associated with said lipoprotein samples because the prior art teaches blood mixed with 1.0% TRITON® X-100 and 0.5% deoxycholate (making obvious the claimed range of about 0.05-0.25% deoxycholate) and the Specification teaches that these amounts are embodiments of the claimed invention. The Specification teaches that as samples are incubated with increasing concentrations of TRITON® X-100 up to 1% and deoxycholate up to 0.5%, more Lp-PLA2 is liberated until it plateaus at those maxima (Specification as filed, Pg. 9, Lines 15-21 and Fig. 5). The Specification as filed further teaches at Pg. 12, Lines 15-16 that an exemplary embodiment of the invention (CHL sample diluent) produces an estimated greater than 95% of released Lp-PLA2. Therefore, the prior art composition would be expected to have the same effects and results as the claimed invention.
With regard to Claims 24 and 27, it would have been obvious to those of ordinary skill in the art before the invention to compile of all the components as claimed into a single location to create a de facto "kit" because this would provide the practitioner with all of the components to practice the method in one discrete location. Those of ordinary skill in the art would have been motivated to make this modification in order to eliminate the need to track down and/or retrieve individual assay components. There would have been a reasonable expectation of success in making this modification because the prior art provides all of the claimed components and compiling them into a discrete location would have been within the skill and purview of those of ordinary skill in the art.
Claim(s) 11, 13, 15, 16, 24, 25, 27, 28, 29, 30, 32, 33, 34, 35, 36 and 38 are rejected under 35 U.S.C. § 103 as being unpatentable over Konrath et al. (US 7,718,380 B2), of record, in view of Zhuo et al. (WO 2015/123598 A1), cited in the IDS, Yang et al. (1997), Terzi et al. (US 2015/0258127 A1) and Jiang et al. (2016), all of record, and further in view of Cojocaru et al. (2010) and Contois et al. (2014), as applied to Claims 11, 13, 15, 24, 25, 27, 28, 29, 32, 33, 34, 35, 36 and 38 above, and further in view of Jardine (2005), of record.
The teachings of Konrath et al., Zhuo et al., Yang et al., Terzi et al., Jiang et al., Cojocaru et al. and Contois et al. were discussed above.
None of the above references taught wherein the sample is from a patient suspected of having, or diagnosed with cardiovascular disease (CVD), as required by Claims 16 and 30.
Jardine teaches that renal transplant patients being treated with tacrolimus have increased risk for CVD (Pg. 380, Column 1, Lines 25-31).
It would have been obvious to those of ordinary skill in the art before the invention that the composition/system of Konrath et al., Zhuo et al., Yang et al., Terzi et al., Jiang et al., Cojocaru et al. and Contois et al. comprising a tacrolimus patient blood serum sample, that the sample be obtained from a patient suspected of having or having CVD, such as a renal transplant patient, because Jardine teaches that renal transplant subjects treated with tacrolimus are at increased risk of CVD. Those of ordinary skill in the art would have been motivated to make this modification because tacrolimus treated renal transplant patients are at risk of having or developing CVD, therefore the ordinary artisan would recognize that this patient population would be at increased risk of having or developing CVD, which should be screened for. There would have been a reasonable expectation of success in making this modification because Konrath et al. teaches the use of tacrolimus treated blood sample and Jardine teaches an association between CVD and tacrolimus treated renal transplant patients.
Claim(s) 11, 13, 15, 24, 25, 26, 27, 28, 29, 31, 32, 33, 34, 35, 36, 37 and 38 are rejected under 35 U.S.C. § 103 as being unpatentable over Konrath et al. (US 7,718,380 B2), of record, in view of Zhuo et al. (WO 2015/123598 A1), cited in the IDS, Yang et al. (1997), Terzi et al. (US 2015/0258127 A1) and Jiang et al. (2016), all of record, and further in view of Cojocaru et al. (2010) and Contois et al. (2014), as applied to Claims 11, 13, 15, 24, 25, 27, 28, 29, 32, 33, 34, 35, 36 and 38 above, and further in view of Wolfert et al. (US 2007/0281323 A1), of record.
The teachings of Konrath et al., Zhuo et al., Yang et al., Terzi et al., Jiang et al., Cojocaru et al. and Contois et al. were discussed above.
None of the above references taught a composition/kit wherein the anti-Lp- PLA2 antibodies are bound to latex microparticles, as required by Claims 26, 31 and 37.
Wolfert et al. teaches a method wherein an Lp-PLA2 containing sample is contacted with an immobilized binder, which specifically binds Lp-PLA2, wherein the immobilized binder is an antibody (Pg. 29, Claims 1 and 3);
and wherein the immobilized binder is bound to a latex bead (Pg. 6, Paragraph [0059]).
The Wolfert reference further teaches that immobilization allowed for a washing step to remove any unbound material or interfering substances (Pg. 6, Paragraph [0060]).
It would have been obvious to those of ordinary skill in the art before the instant invention to modify the composition/system of Konrath et al., Zhuo et al., Yang et al., Terzi et al., Jiang et al., Cojocaru et al. and Contois et al. comprising a patient blood serum sample mixed with a hemolytic/extraction agent containing 1.0% TRITON® X-100 and 0.25% deoxycholate and further comprising anti-Lp-PLA2 antibodies with the immobilization of those antibodies to a latex bead as taught by Wolfert et al., because this would allow for the isolation of Lp-PLA2 in the blood serum sample. Those of ordinary skill in the art before the instant invention would have been motivated to make this modification because the immobilizing allows for a washing step to remove any unbound material or interfering substances. While the Wolfert et al. reference does not indicate that the latex beads are "microparticles", the mere change in size of the latex particles is not sufficient to render them non-obvious as they would still function the same as the prior art latex particles. See the MPEP at 2144.04, IV. A. There would have been a reasonable expectation of success in making this modification because at least both Zhuo et al. and Wolfert et al. are drawn to the use of anti-Lp-PLA2 antibodies.
Response to Arguments
Applicant’s arguments, see Remarks, filed 08/17/2026, with respect to the rejection(s) of claim(s) 11, 13, 15, 16, 22 and 24-38 under 35 U.S.C. § 103 have been fully considered and are persuasive in that the prior cited art did not teach or suggest the new claim limitation of an anti-apoB immune-precipitant.
Therefore, the rejections have been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Cojocaru et al. (2010) and Contois et al. (2014) which addresses and obviates the new limitation.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to PAUL C MARTIN whose telephone number is (571)272-3348. The Examiner can normally be reached Monday-Friday 12pm-8pm EST.
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If attempts to reach the Examiner by telephone are unsuccessful, the Examiner’s supervisor, Sharmila G Landau can be reached at (571) 272-0614. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PAUL C MARTIN/Examiner, Art Unit 1653 09/04/2026
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